Increasing evidence points to inflammation as contributing factor for the pathogenesis of psychopathologies, including depression and anxiety. Work from our collaborative group has established that the inflammatory cytokine interleukin-1 (IL-1) is a crucial mediator of stress induced anxiety. The pathways by which IL-1 induces inflammatory anxiogenesis, however, remain unknown. In this R01 application, we will investigate the novel hypothesis that IL-1 acts on brain endothelial cells to trigger inflammatory microglial activation, which is required for the induction of anxiety behaviors. We will use our newly created IL-1R1 restore mouse lines to study cell type specific IL-1R1 mediated microglial activation and isolate the pathogenic pathways by which IL-1 contributes to anxiogenesis.